Association between Atherosclerotic Diseases and Carboxyhaemoglobin Levels in Tobacco Smokers

In a cross-sectional study carboxyhaemoglobin (COHb) levels in tobacco smokers were found to provide a better indication of a person''s risk of having developed certain atherosclerotic diseases, including ischaemic heart disease, than the smoking history. In the age group 30-69 years a person with a COHb level of 5% or more was found to be 21 times (lower 95% confidence limit 3·3 times) as likely to be affected by these diseases as another person of the same age and sex with similar smoking history and current smoking habits but with a COHb level of less than 3%.     

Effect of cigar smoking on carboxyhaemoglobin and plasma nicotine concentrations in primary pipe and cigar smokers and ex-cigarette smokers

Five ex-cigarette smokers and five primary pipe and cigar smokers each smoked a large cigar. Carboxyhaemoglobin (COHb) and plasma nicotine levels were measured. In the ex-cigarette smokers mean COHb rose from 2·9% to 9·6% and plasma nicotine from 79·0 nmol/l to 281 nmol/l (12·8-45·6 ng/ml). This response was similar to that of cigarette smokers smoking cigarettes, which indicated that the subjects had inhaled and absorbed significant amounts of nicotine. In the primary pipe and cigar smokers the mean COHb rose from 0·8% to 1·0% and the plasma nicotine from 21 nmol/l to 32 nmol/l (3·4-5·2 ng/ml), indicating neither significant inhalation nor significant nicotine absorption.Since ex-cigarette smokers do not seem to lose their habit of inhaling when they change to cigars, measures aimed at persuading smokers to switch to cigars will have little effect on their health. Pipe and cigar smokers who have never smoked cigarettes do not inhale, which probably accounts for their reduced incidence of coronary heart disease and lung cancer. But they also appear not to absorb nicotine, which suggests that nicotine is absorbed largely from the lung and that the buccal mucosa is unimportant. It also raises the interesting question of why primary pipe and cigar smokers do smoke.     

Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers.

Blood nicotine and carboxyhaemoglobin (COHb) concentrations were studied in 330 smokers (206 women and 124 men). Blood nicotine concentrations in individual smokers varied from 25 to 444 nmol/l (4 to 72 ng/ml). The average concentration, 203 nmol/l (33 ng/ml), was the same in the men and the women, although cigarette consumption was higher in the men. Despite large differences in nicotine yield, there was no relation between blood nicotine concentration and the type of cigarette smoked: smokers of plain, untipped cigarettes (1.9 mg nicotine), cigarettes with unventilated filters (1.3 mg nicotine), and cigarettes with ventilated filters (0.8 mg nicotine) had similar blood nicotine concentrations. Cigarette consumption was also similar in these three groups. The correlation between blood nicotine concentration and nicotine yield of cigarette, though significant, was low (0.21, p < 0.001), showing that the nicotine yield of the cigarettes accounted for only 4.4% of the variation in blood nicotine concentrations. Similarly, the low correlation of 0.30 between COHb concentration and cigarette consumption suggests that cigarette consumption accounted for only 9% of the variation in the amount of smoke taken into the smokers'' lungs. These results suggest that the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation. The findings of epidemiological studies showing lower risks with filter-tipped cigarettes may be attributable to other factors such as biases in the samples and changes in the quality and carcinogenicity of tobacco tar, rather than to reduced tar intake.     

Effects of stopping smoking for 48 hours on oxygen availability from the blood: a study on pregnant women.

The effects of stopping smoking for 48 hours on factors governing the availability of oxygen from the blood--that is, carboxyhaemoglobin (COHb), haemoglobin-oxygen (HbO2) affinity, and haemoglobin concentration--were measured in women in the last trimester of pregnancy. Three groups were studied: smokers, smokers who stopped smoking for 48 hours, and non-smokers. The 22 smokers had higher initial COHb values and greater HbO2 affinity than the 10 non-smokers, but their total haemoglobin concentrations were also higher, so that their oxygen availability was not significantly reduced. In the 11 smokers who stopped the reduction in COHb and decrease in HbO2 affinity led to a significant increase of 8% in "available oxygen" in 48 hours. Since even small improvements in oxygen delivery to the tissues may confer critical benefit to the fetus, particularly during labour or when exposed to general anaesthesia, smoking should be discouraged for 48 hours before elective deliveries. The same consideration might reasonably be applied to patients undergoing general anaesthesia for all elective operations.     

Relationship between cigarette yields,puffing patterns,and smoke intake: evidence for tar compensation?

The relationship between cigarette yields (of nicotine, tar, and carbon monoxide), puffing patterns, and smoke intake was studied by determining puffing patterns and measuring blood concentrations of nicotine and carboxy-haemoglobin (COHb) in a sample of 55 smokers smoking their usual brand of cigarette. Regression analyses showed that the total volume of smoke puffed from a cigarette was a more important determinant of peak blood nicotine concentration than the nicotine or tar yield of the cigarette, its length, or the reported number of cigarettes smoked on the test day. There was evidence of compensation for a lower tar yield over and above any compensation for nicotine. When nicotine yield was controlled for, smokers of lower-tar cigarettes not only puffed more smoke from their cigarettes than smokers of higher-tar cigarettes but they also had higher plasma nicotine concentrations, suggesting that they were compensating for the reduced delivery of tar by puffing and inhaling a greater volume of smoke. The results based on the COHb concentrations were consistent with this interpretation. If an adequate intake of tar proves to be one of the main motives for smoking, then developing a cigarette that is acceptable to smokers and also less harmful to their health will be much more difficult.     

Should intake of carbon monoxide be used as a guide to intake of other smoke constituents?

The relation between blood carboxyhaemoglobin (COHb) and plasma nicotine concentrations was studied in a group of 12 smokers smoking cigarettes of three levels of standard delivery. While the intake of carbon monoxide from a single cigarette was unrelated to the intake of nicotine, presmoking "trough" concentrations of the two substances (reflecting longer-term exposure) were highly correlated. Various other measures of nicotine exposure were at best only moderately correlated with blood nicotine concentrations. Thus trough COHb concentrations might be used to provide a reliable indication of the exposure to nicotine of individual smokers smoking the same type of cigarette, and of the relative exposure to nicotine of populations smoking cigarettes of different standard deliveries.     

Cigarette smoking during pregnancy lowers aromatase cytochrome P-450 in the human placenta

To clarify whether cigarette smoking during pregnancy causes an organic alteration in placental estrogen producing ability, we determined the catalytic activity of aromatase by the tritiated water assay, and tissue level of aromatase cytochrome P-450 (P-450_arom) by the specific enzyme-linked immunosorbent assay, in placental samples from nonsmokers and smokers. As pregnancy progressed, both aromatase activity and P-450_arom concentration increased in placentas from nonsmokers and smokers. However, the gradient of the increase was significantly less in heavy smokers (20 cigarettes a day) than in normal and moderate smokers (<20 cigarettes a day). At term, the mean aromatase activity and P-450_arom concentration in placentas from heavy smokers were significantly lower than in nonsmokers and moderate smokers, while aromatase activity per P-450_arom (turnover rate) and the mean placental weight were comparable among the three groups. In contrast, the ratio of aryl hydrocarbon hydroxylase activity to aromatase activity was higher in placentas from heavy smokers. Immunohistochemical studies showed that P-450_arom was localized in the cytoplasm of syncytiotrophoblasts of chorionic villi in placentas from both nonsmokers and smokers. These results suggest that the induction of placental P-450_arom during gestation is suppressed by maternal smoking, resulting in a reduction in estrogen producing ability, while placental xenobiotic P-450 is induced.     

Heme oxygenase activity increases after exercise in healthy volunteers

Heme oxygenase (HO) is an essential, rate-limiting protein which catalyses the breakdown of heme to iron, carbon monoxide (CO), and biliverdin. The alpha methene bridge of the heme is eliminated as CO which can be measured as blood carboxyhaemoglobin (COHb). Using blood concentrations of COHb as a measure reflecting HO activity, we tested the postulate that the activity of HO changes with exercise. Ten healthy, nonsmoking volunteers (5 females and 5 males with a mean age?±?standard deviation of 25.7?±?3.2 years), lifetime nonsmokers with no history of respiratory diseases and not taking any medication, were included in the study. Subjects were exposed to filtered air for 2?hrs while alternating exercise for 15?minutes on a cycle ergometer with rest for 15?minutes. Workload was adjusted so that subjects breathed at a ventilatory rate, normalised for body surface area, of 25?L/m²/minute. Immediately before, immediately after, and the day following exercise, blood was drawn by standard venipuncture technique. COHb was determined using the interleukin (IL) 682 Co-Oximeter (Instrumentation Laboratory, Bedford, MA). COHb increased in each participant during the exercise session with the mean value (± standard deviation) almost doubling (1.1?±?1.6 to 2.1?±?1.6%) and returned to baseline by the following day (1.3?±?1.3%). We conclude that exercise increases HO activity.     

Self-titration by cigarette smokers

An 11-week crossover study was carried out in which 12 subjects smoked high-nicotine (1·84 mg standard yield) and low-nicotine (0·6 mg) cigarettes after an initial period of smoking their usual brands with a medium-nicotine yield (mean 1·4 mg). Plasma and urine nicotine concentrations, carboxyhaemoglobin (COHb) concentration, puffing behaviour, 24-hour cigarette consumption, and butt nicotine content were measured. The changes in plasma nicotine and blood COHb concentrations showed that the smokers compensated for about two-thirds of the difference in standard yields when switched to either high- or low-nicotine cigarettes. Thus, compared with the medium-nicotine brand, the intake of nicotine and carbon monoxide was only about 10% higher when subjects smoked the high-nicotine cigarettes, which had a standard yield 30-40% higher than the medium brands; and only about 15% lower when they smoked the low-nicotine cigarettes, which had a standard yield about 50% lower than the medium brands. But nicotine content and urine nicotine concentrations followed a similar pattern. Changes in puffing behaviour and in 24-hour cigarette consumption were only slight.The results show clear evidence of both upward and downward self-titration of nicotine and carbon monoxide (and tar) intakes when smokers change to cigarettes with standard yields that differ over the range studied.     

Age,smoking habits,heat stress,and their interactive effects with carbon monoxide and peroxyacetylnitrate on man's aerobic power

Metabolic, body temperature, and cardiorespiratory responses of 16 healthy middle-aged (40–57 years) men, 9 nonsmokers and 7 smokers, were obtained during tests of maximal aerobic power at ambient environmental temperatures of 25 ± 0.5 and 35 ± 0.5°C and 20% relative humidity under four conditions: (a) filtered air, FA; (b) 50 ppm carbon monoxide in filtered air, CO; (c) 0.27 ppm peroxyacetylnitrate in filtered air, PAN; and (d) a combination of all three mixtures, PANCO. There was no significant change in maximum aerobic power \(\left( {\dot VO2max} \right)\) related to the presence of air pollutants, although total working time was lowered in the 25°C environment while breathing CO. Older nonsmokers did have a decrement in \(\left( {\dot VO2max} \right)\) while breathing 50 ppm CO, while older smokers failed to show any change. This difference was related to the initial COHb levels of the smokers, who, when breathing this level of ambient CO, had only a 14% increase in COHb over their initial levels in contrast to the 200% increase in the nonsmokers. Smoking habits were the most influential factor affecting the cardiorespiratory responses of these older men to maximal exercise. Regardless of ambient conditions, smokers had a significantly lower (27%) aerobic power than nonsmokers, were breathing closer to their maximal breathing capacities throughout the walk, and had a higher respiratory exchange ratio. While the \(\left( {\dot VO2max} \right)\) of nonsmokers was only 6% less than that of younger nonsmoking males ( \(\bar x\) age = 25 years) working under similar conditions, the aerobic power of the older smokers was 26% lower than that of young smokers ( \(\bar x\) age = 24 years).     

Is carbon monoxide-mediated cyclic guanosine monophosphate production responsible for low blood pressure in neonatal respiratory distress syndrome?

Infant respiratory distress syndrome (RDS) involves inflammatory processes, causing an increased expression of inducible heme oxygenase with subsequent production of carbon monoxide (CO). We hypothesized that increased production of CO during RDS might be responsible for increased plasma levels of vasodilatory cGMP and, consequently, low blood pressure observed in infants with RDS. Fifty-two infants (no-RDS, n = 21; RDS, n = 31), consecutively admitted to the neonatal intensive care unit (NICU) between January and October 2003 were included. Hemoglobin-bound carbon monoxide (COHb), plasma cGMP, plasma nitric oxide (NOx), and bilirubin were determined at 0-12, 48-72, and at 168 h postnatally, with simultaneous registration of arterial blood pressure. Infants with RDS had higher levels of cGMP and COHb compared with no-RDS infants (RDS vs. no-RDS: cGMP ranging from 76 to 101 vs. 58 to 82 nmol/l; COHb ranging from 1.2 to 1.4 vs. 0.9 to 1.0%). Highest values were reached at 48-72 h [RDS vs. no-RDS mean (SD): cGMP 100 (39) vs. 82 (25) nmol/l (P < 0.001); COHb 1.38 (0.46) vs. 0.91 (0.26)% (P < 0.0001)]. Arterial blood pressure was lower and more blood pressure support was needed in RDS infants at that point of time [RDS vs. no-RDS mean (SD): mean arterial blood pressure 33 (6) vs. 42 (5) mmHg (P < 0.05)]. NOx was not different between groups and did not vary with time. Multiple linear regression analysis showed a significant correlation between cGMP and COHb, suggesting a causal relationship. Mean arterial blood pressure appeared to be primarily correlated to cGMP levels (P < 0.001). We conclude that a CO-mediated increase in cGMP causes systemic vasodilation with a consequent lower blood pressure and increased need for blood pressure support in preterm infants with RDS.     

Peak expiratory flow in symptomless elderly smokers and ex-smokers.

Values of peak expiratory flow (PEF) in 142 current smokers (116 men, 26 women) and 108 ex-smokers (88 men, 20 women) aged 55 or over were compared with the predicted values obtained in lifelong nonsmokers of the same age range. None of the subjects had been liable during childhood or subsequently to expectoration, lower respiratory tract infection, wheeze, or shortness of breath. Observed values of PEF were expressed as differences from predicted. Analysis of the relation between smoking state and ventilatory function in the men disclosed significant reductions of PEF in current smokers, the deficits increasing with the amount smoked from a mean of 48.1 l/min in those smoking fewer than 20 cigarettes a day to 73.3 l/min in smokers of 20 or more a day. Significant reductions of PEF were also found in women who were currently smoking (mean 47.4 l/min) and in male ex-smokers of 20 or more cigarettes a day (mean 27.8 l/min). There was no significant reduction of PEF in male or female ex-smokers of fewer than 20 cigarettes a day. These findings suggest that factors besides smoking are concerned in the development of irreversible airflow obstruction.     

Ranked set sampling for replicated sampling designs

In practical ecological sampling studies, a certain design (such as plot sampling or line-intercept sampling) is usually replicated more than once. For each replication, the Horvitz-Thompson estimation of the objective parameter is considered. Finally, an overall estimator is achieved by averaging the single Horvitz-Thompson estimators. Because the design replications are drawn independently and under the same conditions, the overall estimator is simply the sample mean of the Horvitz-Thompson estimators under simple random sampling. This procedure may be wisely improved by using ranked set sampling. Hence, we propose the replicated protocol under ranked set sampling, which gives rise to a more accurate estimation than the replicated protocol under simple random sampling.     

Sister-chromatid exchange and cell proliferation in cultured lymphocytes of passively and actively smoking restaurant personnel

Sister-chromatid exchange frequencies were measured in peripheral lymphocytes of 12 cigarette smokers, 20 passive smokers, and 14 non-smokers with no regular exposure to tobacco smoke. All active and passive smokers worked as waiters and waitresses in restaurants. The passive smokers showed neither an increased mean SCE value nor an increased number of high SCE frequency cells (HFCs) when compared to non-exposed non-smokers. The incidence of SCEs and HFCs was observed to be elevated (P less than 0.01; P less than 0.05, resp.) among the active smokers. The proliferation rate of lymphocytes in whole blood cultures from the different exposure groups was also studied. The proportion of cells in first mitosis was lower and the mean replication index (RI) higher among the smokers than among non-smoker controls. However, no significant correlation was observed between the individual mean SCE and the replication index.     

Leukaemia and smoking habits among United States veterans.

The relation between leukaemia and smoking habits was examined in data from the veterans'' smoking study, a prospective study of mortality among 248,000 United States veterans, of whom 723 died of leukaemia during 1954-69. A significant increase in mortality from leukaemia among cigarette smokers (relative risk 1.53) was found, together with a dose-response relation with amount smoked (trend p less than 0.001). The relation was strongest (relative risk 1.72) for monocytic and chronic and unspecified myeloid leukaemias (ICD (7th revision) codes 204.1 and 204.2). For these leukaemias the increase was almost twofold (relative risk 1.93) among current smokers of over 20 cigarettes daily. Ex-cigarette smokers also showed an increase of leukaemia (relative risk 1.39; p less than 0.001). These findings are consistent with other studies and relevant to the interpretation of minor increases of leukaemia both in population and in individual based studies. If causal they also imply that smoking is responsible for many more deaths from leukaemia in adults than all other known causes combined.     

Incorporating patterns of disperser behaviour into models of seed dispersal and its effects on estimated dispersal curves

The processes determining where seeds fall relative to their parent plant influence the spatial structure and dynamics of plant populations and communities. For animal dispersed species the factors influencing seed shadows are poorly understood. In this paper we test the hypothesis that the daily temporal distribution of disperser behaviours, for example, foraging and movement, influences dispersal outcomes, in particular the shape and scale of dispersal curves. To do this, we describe frugivory and the dispersal curves produced by the southern cassowary, Casuarius casuarius, the only large-bodied disperser in Australia’s rainforests. We found C. casuarius consumed fruits of 238 species and of all fleshy-fruit types. In feeding trials, seeds of 11 species were retained on average for 309 min (±256 SD). Sampling radio-telemetry data randomly, that is, assuming foraging occurs at random times during the day, gives an estimated average dispersal distance of 239 m (±207 SD) for seeds consumed by C. casuarius. Approximately 4% of seeds were dispersed further than 1,000 m. However, observation of wild birds indicated that foraging and movement occur more frequently early and late in the day. Seeds consumed early in the day were estimated to receive dispersal distances 1.4 times the ‘random’ average estimate, while afternoon consumed seeds received estimated mean dispersal distances of 0.46 times the ‘random’ estimate. Sampling movement data according to the daily distribution of C. casuarius foraging gives an estimated mean dispersal distance of 337 m (±194 SD). Most animals’ behaviour has a non-random temporal distribution. Consequently such effects should be common and need to be incorporated into seed shadow estimation. Our results point to dispersal curves being an emergent property of the plant–disperser interaction rather than being a property of a plant or species.     

A mathematical model for the computation of carboxyhaemoglobin in human blood as a function of exposure time.

A mathematical model is developed for the carbon monoxide (CO) uptake by the blood by taking into account the molecular diffusion, convection, facilitated diffusion and the non-equilibrium kinetics of CO with haemoglobin. The overall rate for the combination of CO with haemoglobin is derived by including the dissociation of CO from carboxyhaemoglobin (COHb). The resulting coupled system of nonlinear partial differential equation with physiologically relevant initial, entrance and boundary conditions is solved numerically. A fixed point iterative technique is used to deal with nonlinearities. The concentration of COHb in the blood is computed as a function of exposure time and ambient CO concentration. The COHb levels computed from our model are in good agreement with those measured experimentally. Also, results computed from our model give better approximation to the experimental values compared with the results from other models. The time taken by the blood COHb to attain 95% of its equilibrium value is computed. The COHb concentration in the blood increases with the increase in ventilation rate, association rate coefficient of CO with haemoglobin and total haemoglobin content in the blood, and with the decrease in dissociation rate coefficient of CO with haemoglobin and mean capillary blood PO2. It is found that the COHb level in the blood is not affected significantly because of endogenous production of CO in the body under normal condition. However, the effect may be significant in the patients with haemolytic anaemia.     

Effectiveness of a nicotine patch in helping people stop smoking: results of a randomised trial in general practice. Imperial Cancer Research Fund General Practice Research Group.

OBJECTIVE--To assess the effectiveness of 12 weeks'' treatment with a 24 hour transdermal nicotine patch in helping heavy smokers to stop smoking; also to assess the value of a specially written support booklet about smoking cessation and patch use compared with a simple advice pamphlet. DESIGN--Double blind placebo controlled randomised trial with a 2 x 2 factorial design. SETTING--19 general practices in Oxfordshire. SUBJECTS--1686 heavy smokers aged 25-64 (mean cigarette consumption 24/day; mean duration of smoking 25 years). MAIN OUTCOME MEASURE--Sustained cessation for the last four weeks of the 12 week treatment period, confirmed by saliva cotinine estimation (226/262 cases; 86.3%) or expired carbon monoxide concentration (36/262; 13.7%). Patients lost to follow up (155/1686; 9%) were assumed to have continued to smoke. RESULTS--Cessation was confirmed in 163 patients (19.4%) using the nicotine patch and 99 patients (11.7%) using the placebo patch (difference 7.6% (95% confidence interval 4.2% to 11.1%); p < 0.0001). There was no significant advantage in using the more detailed written support material. The most important adverse effect of the patch was local skin irritation, which occurred in 15.8% (133/842) and 5.1% (43/844) of patients using the nicotine and placebo patches respectively, was graded as severe in 4.8% (40) and 1.1% (nine), and was stated as a reason for withdrawal from the trial in 9.5% (80) and 2.8% (24). CONCLUSION--Nicotine patches are effective in a general practice setting with nursing support, but the extent to which this effect is sustained cannot be assessed until the results of longer term follow up are known.     

Plasma oxytocin concentrations during late pregnancy and parturition in the dog

While oxytocin is widely used in the treatment of dystocia in dogs, there is little information about its secretion before and during normal unassisted whelping. We therefore measured plasma oxytocin concentrations during late pregnancy and the expulsive stage of parturition. Blood samples were collected from eight dogs at 3-min intervals during a 42-min period between the 2nd and 14th day before whelping and during parturition after the birth of 1-3 pups. The litters consisted of 5-15 pups and the progression of the expulsive stage was linear and nearly parallel in the eight bitches. The overall mean (+/-S.D.) plasma oxytocin concentration during late pregnancy was 3.6+/-2.1pg/ml. Mean values in individual dogs ranged from 1.2 to 7.4 pg/ml, but the intra-animal variation was rather small. During the expulsive stage the overall mean (+/-S.D.) plasma oxytocin concentration was 12.9+/-13.9 pg/ml, with mean values in individual dogs ranging from 3.5 to 46 pg/ml. The mean area under the oxytocin curve for parturient dogs was significantly higher (P<0.05) than for pregnant dogs. During the expulsive stage, the peak plasma oxytocin level in individual dogs ranged between 10 and 117 pg/ml. In six of the eight dogs a pup was born during blood collection and in five of these animals the plasma oxytocin concentration increased temporarily during periods of abdominal straining and expulsion. However, straining efforts and expulsion were not consistently associated with a rise in the circulating oxytocin level. It is concluded that in the dog plasma oxytocin levels are higher and more variable during the expulsive stage of parturition than during late pregnancy. Interrelationships between the secretion pattern of oxytocin, the level of uterine contractility, and the progress of fetal expulsion in dogs need further exploration.     

Effect of nicotine chewing gum on smoking behaviour and as an aid to cigarette withdrawal.

In a double-blind, placebo-controlled, crossover trial the effect of 2-mg nicotine chewing gum was studied in 43 smokers when they were smoking as inclined and when they were trying to stop smoking. Although 70% of the smokers stopped smoking during treatment, only 23% were still abstinent after one year. The effect of the nicotine, though significant, was small compared with the overall reduction in smoking. When the subjects were smoking as inclined cigarette consumption was reduced by an average of 37% on the nicotine gum compared with 31% on placebo gum, while avergage carboxyhaemoglobin (COHb) levels were reduced by 26% and 15% on the active and placebo gums respectively. When subjects tried to stop smoking there was a further considerable reduction in cigarette consumption, but no longer any difference between the two gums. Nevertheless, average COHb was still lower on the active gum. Plasma nicotine levels on the nicotine gum averaged only 10-7 ng/ml compared with 27-4 ng/ml after smoking. Better results could be expected with 4-mg nicotine gums.